The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure

Objectives. We sought to identify the effects of endothelin (ET) subtype-A (ETA) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility. Background. Congested heart failure causes increased plasma levels of ET and ETA receptor activation. Methods. Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n = 7; 2) CHF/ETA-High Dose: paced for 2 weeks then ETA receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n = 6; 3) CHF/ETA-Low Dose: pacing for 2 weeks then ETA receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n = 6; and 4) Control: n = 8. Results. Left ventricle fractional shortening decreased with CHF compared with control (12 +/- 1 vs. 39 a 1%, p < 0.05) and increased in the CHF/ETA High and Low Dose groups (23 +/- 3 and 25 +/- 1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ETA receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ETA High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ETA blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32 3 vs. 54 +/- 3 mu m/s, p < 0.05), was higher in the CHF/ETA High Dose group (39 +/- 1 mu m/s, p < 0.05), and was similar to CHF values in the Low Dose group. Conclusions. ETA receptor activation may contribute to the progression of LV dysfunction with CHF. (J Am Cell Cardiol 1998;32:1779-86) (C) 1998 by the American College of Cardiology.